{
  "abstract": "Background While chimeric antigen receptor (CAR) T cells have achieved encouraging remission rates in hematological malignancies, they have demonstrated limited success in treating glioblastoma (GBM), particularly due to high intratumoral and intertumorous heterogeneity. In this study, we identified a consistently expressed target antigen, podoplanin (PDPN), and evaluated the potential of a PDPN-CAR T cell and GD2-CAR T cell blend to target heterogeneous GBM.Methods Target antigen screening included clinical samples, cell lines and healthy tissues, as well as public RNA sequencing datasets. The anti-tumor function of CAR T cells was examined in co-culture experiments with GBM cell lines and patient-derived organoids (PDOs), and in vivo after locoregional delivery in orthotopic xenograft models.Results CAR T cells demonstrated strong anti-tumor activity against several cell lines and PDOs from multiple patients. PDPN and GD2 were expressed in all PDOs, and regardless of the antigen expression pattern, the CAR T cell blend induced significantly higher apoptosis levels in organoids compared with single-antigen targeting CAR T cells. In vivo, we observed efficient tumor regression after locoregional administration of monospecific CAR T cells. While heterogeneous orthotopic tumors eventually relapsed in these groups, therapy with the CAR T cell blend significantly increased overall survival and even achieved a cure in the majority of mice.Conclusion This novel PDPN/GD2 CAR T cell blend demonstrated robust efficacy in advanced preclinical GBM models, suggesting its potential to treat heterogeneous GBM and address limitations associated with single-antigen CAR T cell therapies.",
  "authors": [
    {
      "affiliations": [
        "Chair of Cellular Immunotherapy, Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany"
      ],
      "name": "Julian Hübner"
    },
    {
      "affiliations": [
        "Department of Neurosurgery, Section Experimental Neurosurgery, University Hospital Würzburg, Würzburg, Germany"
      ],
      "name": "Marah Alsalkini"
    },
    {
      "affiliations": [
        "Department of Neurology, University Hospital Würzburg, Würzburg, Germany"
      ],
      "name": "Rhonda McFleder"
    },
    {
      "affiliations": [
        "Chair of Cellular Immunotherapy, Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany"
      ],
      "name": "Fabio Toppeta"
    },
    {
      "affiliations": [
        "Department of Neurosurgery, Section Experimental Neurosurgery, University Hospital Würzburg, Würzburg, Germany"
      ],
      "name": "Julia Wagner"
    },
    {
      "affiliations": [
        "Department of Nephropathology, University of Erlangen-Nürnberg, Erlangen, Germany",
        "Institute of Pathology, University of Erlangen-Nürnberg, Erlangen, Germany"
      ],
      "name": "Renato Liguori"
    },
    {
      "affiliations": [
        "Chair of Cellular Immunotherapy, Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany"
      ],
      "name": "Björn Grams"
    },
    {
      "affiliations": [
        "Department of Neurosurgery, Section Experimental Neurosurgery, University Hospital Würzburg, Würzburg, Germany"
      ],
      "name": "Moritz Meyer-Hofmann"
    },
    {
      "affiliations": [
        "Department of Neurosurgery, Section Experimental Neurosurgery, University Hospital Würzburg, Würzburg, Germany"
      ],
      "name": "Leopold Diener"
    },
    {
      "affiliations": [
        "Department of Neuropathology, Institute of Pathology, University of Würzburg, Würzburg, Germany"
      ],
      "name": "Camelia-Maria Monoranu"
    },
    {
      "affiliations": [
        "Department of Neurosurgery, Section Experimental Neurosurgery, University Hospital Würzburg, Würzburg, Germany"
      ],
      "name": "Carsten Hagemann"
    },
    {
      "affiliations": [
        "Department of Nephropathology, University of Erlangen-Nürnberg, Erlangen, Germany",
        "Institute of Pathology, University of Erlangen-Nürnberg, Erlangen, Germany"
      ],
      "name": "Fulvia Ferrazzi"
    },
    {
      "affiliations": [
        "Department of Neurology, University Hospital Würzburg, Würzburg, Germany"
      ],
      "name": "Chi Wang Ip"
    },
    {
      "affiliations": [
        "Bavarian Center for Cancer Research (BZKF), Würzburg, Germany",
        "Department of Neurosurgery, University Hospital Würzburg, Würzburg, Germany",
        "Site Würzburg-Erlangen-Regensburg-Augsburg (WERA), National Center for Tumor Diseases (NCT), Würzburg, Germany"
      ],
      "name": "Ralf-Ingo Ernestus"
    },
    {
      "affiliations": [
        "Bavarian Center for Cancer Research (BZKF), Würzburg, Germany",
        "Site Würzburg-Erlangen-Regensburg-Augsburg (WERA), National Center for Tumor Diseases (NCT), Würzburg, Germany",
        "Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany"
      ],
      "name": "Hermann Einsele"
    },
    {
      "affiliations": [
        "Chair of Cellular Immunotherapy, Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany",
        "Bavarian Center for Cancer Research (BZKF), Würzburg, Germany",
        "Site Würzburg-Erlangen-Regensburg-Augsburg (WERA), National Center for Tumor Diseases (NCT), Würzburg, Germany",
        "Branch Site Cellular Immunotherapy, Fraunhofer Institute for Cell Therapy and Immunology (IZI), Würzburg, Germany"
      ],
      "name": "Michael Hudecek"
    },
    {
      "affiliations": [
        "Department of Neurosurgery, Section Experimental Neurosurgery, University Hospital Würzburg, Würzburg, Germany"
      ],
      "name": "Mario Löhr"
    },
    {
      "affiliations": [
        "Chair of Cellular Immunotherapy, Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany"
      ],
      "name": "Thomas Nerreter"
    },
    {
      "affiliations": [
        "Department of Neurosurgery, Section Experimental Neurosurgery, University Hospital Würzburg, Würzburg, Germany"
      ],
      "name": "Vera Nickl"
    }
  ],
  "title": "Novel CAR T cell blend targeting PDPN and GD2 to overcome glioblastoma heterogeneity",
  "uid": "06f3d9f3-66a2-527d-8b7f-186d330b5d07"
}